Various patents and other publications are referred to throughout the specification. Each of these publications is incorporated by reference herein, in its entirety.
Neurological diseases and other disorders of the central and peripheral nervous system are among the most debilitating that can be suffered by an individual, not only because of their physical effects, but also because of their permanence. In the past, a patient suffering from brain or spinal cord injury, or a neurodegenerative condition of the central or peripheral nervous system, such as Parkinson's disease, Alzheimer's disease or multiple sclerosis, to name a few, held little hope for recovery or cure.
Neurological damage and neurodegenerative diseases were long thought to be irreversible because of the inability of neurons and other cells of the nervous system to grow in the adult body. However, the adult mammalian brain retains some capacity for plasticity and neuronal regeneration following injury. (See, Kolb, B, Can J Exp Psycho, 1999; 53:62-76; Stroemer, R P, et al., Stroke, 1998; 29:2381-93; Walter, D H, et al., Circulation, 2002; 105(25):3017-24; Plate, K H, J Neuropathol Exp Neurol, 1999; 58(4):313-20; Szpak, G M, et al., Folia Neuropathol, 1999; 37(4):264-8; Jin, K, et al., Proc Natl Acad Sci USA, 2001; 98(8):4710-5; Parent, J M, et al., Ann Neurol, 2002; 52(6):802-13; Stroemer, R P, et al., Stroke, 1995; 26(11):2135-44; Keyvani, K, et al., J Neuropathol Exp Neurol, 2002; 61(10):831-40; Lois, C, et al., Science, 1996; 271(5251):978-81; and, Dutton, R, et al., Dev Neurosci, 2000; 22(1-2):96-105). For example, the subventricular zone (SVZ) contains a population of cells capable of undergoing differentiation into various cell types, including neurons, (See, Chen, J, et al., Stroke, 2001; 32:1005-1011; Evers, B M, et al., J Am Coll Surg, 2003; 197:458-478; Seyfried, D, et al., J Neurosurg, 2006; 104:313-318) and experiments of ischemic injury and traumatic brain injury (TBI) suggest that cells in this region participate in the recovery process. Both clinical studies and animal models suggest that there are several mechanisms involved in cellular injury following intracranial hemorrhage (ICH). These include a traumatic or mechanical component, an ischemic component, and direct toxic effects of a blood clot. (See, Gong, C, et al., Neurosurgery, 2001; 48:875-883; Gong, C, et al., Brain Res, 2000; 871:57-65; Hua, Y, et al., J Cereb Blood Flow Metab, 2002; 22:55-61; Matsushita, K, et al., J Cereb Blood Flow Metab, 2000; 20:396-404; Xi, G, et al., Stroke, 2001; 32:2932-2938; and, Seyfried, D, et al., J Neurosurg, 2004; 101:104-107). Clinically, ICH occurs in close proximity to the ventricular system and therefore, recovery from injury after ICH may involve the SVZ.
Additionally, the recent advent of stem cell-based therapy for tissue repair and regeneration provides promising treatments for a number of neurodegenerative pathologies and other neurological disorders. Stem cells are capable of self-renewal and differentiation to generate a variety of mature neural cell lineages. Transplantation of such cells can be utilized as a clinical tool for reconstituting a target tissue, thereby restoring physiologic and anatomic functionality. The application of stem cell technology is wide-ranging, including tissue engineering, gene therapy delivery, and cell therapeutics, i.e., delivery of biotherapeutic agents to a target location via exogenously supplied living cells or cellular components that produce or contain those agents.
Stem cells with neural potency have been isolated from adult tissues. For example, neural stem cells exist in the developing brain and in the adult nervous system. These cells can undergo expansion and can differentiate into neurons, astrocytes and oligodendrocytes. However, adult neural stem cells are rare, as well as being obtainable only by invasive procedures, and may have a more limited ability to expand in culture than do embryonic stem cells.
Other adult tissue may also yield progenitor cells useful for cell-based neural therapy. For instance, it has been reported recently that adult stem cells derived from bone marrow and skin can be expanded in culture and give rise to multiple lineages, including some neural lineages.
Postpartum tissues, such as the umbilical cord, have generated interest as an alternative source of stem cells. For example, methods for recovery of stem cells by perfusion of the placenta or collection from umbilical cord blood or tissue have been described. A limitation of stem cell procurement from these methods has been an inadequate volume of cord blood or quantity of cells obtained, as well as heterogeneity in, or lack of characterization of, the populations of cells obtained from those sources.
Additionally, neuroregeneration by mesencyhmal stem cells (MSC) after cerebral ischemia is associated with elevated levels of growth factors such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) localized to the area of the injury. In regions of the brain surrounding experimental infarction, it has been shown that there is increased microvessel formation and evidence of cells migrating along the microvessels, particularly cells from the SVZ. (See, Evers, B M, et al., J Am Coll Surg, 2003; 197:458-478). Also, it has been shown that MSC are associated with increased synaptogenesis, so that newly formed, or recovering cells exhibit more connections, which is consistent with the observation of improved functional recovery. (See, Seyfried, D, et al., J Neurosurg, 2006; 104:313-318). The cellular recovery process may be aided by the removal of debris and/or secretion of growth factors, thereby creating an environment inducive to neuronal cell regeneration. Given the debilitating nature of neurological injury there is a need to develop cellular regenerative therapies to aid in recovery.